A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

Abstract

Purpose: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates. Procedures: Positron emission tomography (PET) measurements with (R)-[11 C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V T ) and V T /fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.Results: The brain uptake of (R)-[ 11 C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose-and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/ kg of roflumilast, regardless of outcome measures, V T or V T /fp. Conclusions: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates.Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…Apart from that, the obtained data may suggest that 30-40% of in vivo brain PDE4 occupancy, which corresponds to the clinical dose of roflumilast, might be an acceptable level of PDE4 inhibition not to induce severe nausea and emesis [48]. Further (pre-)clinical studies are required to investigate the relationship between roflumilast treatment, PDE4 occupancy in the brain, effects on cognitive domains, and occurrence of nausea and emesis [48]. For that purpose, Takano et al suggested that PET studies using subtype-specific PDE4 radioligands instead of [ 11 C]rolipram would be more effective to understand the function of the PDE4 isoforms [48].…”

“…Roflumilast is the first PDE4 inhibitor that has been approved for treatment of severe chronic obstructive pulmonary disease (COPD) [50]. In roflumilast-treated rhesus monkeys, a reduced [ 11 C]rolipram accumulation in all brain regions, a faster washout and a decreased V T have been observed [48]. These results indicate that roflumilast is brainpenetrant and shows a dose-dependent PDE4 binding.…”

“…The estimated PDE4 occupancy was <50% even at a dose of 200 µg/kg. Thus, Takano et al stated that higher doses of roflumilast would be needed to confirm whether in vivo maximal PDE4 occupancy as measured with [ 11 C]rolipram can reach 100% [48]. Apart from that, the obtained data may suggest that 30-40% of in vivo brain PDE4 occupancy, which corresponds to the clinical dose of roflumilast, might be an acceptable level of PDE4 inhibition not to induce severe nausea and emesis [48].…”

“…Thus, Takano et al stated that higher doses of roflumilast would be needed to confirm whether in vivo maximal PDE4 occupancy as measured with [ 11 C]rolipram can reach 100% [48]. Apart from that, the obtained data may suggest that 30-40% of in vivo brain PDE4 occupancy, which corresponds to the clinical dose of roflumilast, might be an acceptable level of PDE4 inhibition not to induce severe nausea and emesis [48]. Further (pre-)clinical studies are required to investigate the relationship between roflumilast treatment, PDE4 occupancy in the brain, effects on cognitive domains, and occurrence of nausea and emesis [48].…”

“…Further (pre-)clinical studies are required to investigate the relationship between roflumilast treatment, PDE4 occupancy in the brain, effects on cognitive domains, and occurrence of nausea and emesis [48]. For that purpose, Takano et al suggested that PET studies using subtype-specific PDE4 radioligands instead of [ 11 C]rolipram would be more effective to understand the function of the PDE4 isoforms [48].…”